Cyclopropylamine → N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamide

HRID 1697284Notes

Reaction equation

HRID 1697284 reaction equation
Br[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6](Br)[N:7]=1.C([N:24](CC)[CH:25]([CH3:27])[CH3:26])(C)C.[NH2:30][C@@H:31]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]2C=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:34][CH2:33]1.[CH:54]1([NH2:57])[CH2:56][CH2:55]1.C1([Mg]Br)CCCC1>O1CCCC1.C(OCC)(=O)C.C(O)C>[CH:25]1([NH:24][C:12](=[O:14])[C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:30][C@@H:31]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:32]4[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]4)[C:3]3=[O:20])[CH:10]=2)[CH2:27][CH2:26]1.[CH:54]1([NH:57][C:12]([C:11]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:9]([N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:30][C@@H:31]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]5[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=5)=[O:39])[CH2:34][CH2:33]4)[C:3]3=[O:20])[CH:10]=2)=[O:14])[CH2:56][CH2:55]1

Participants

10

Reactant 5

HCID 69828CyclopropylamineHCID 81531DiisopropylethylamineHCID 66688740methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoateHCID 666897524-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid phenylmethyl esterHCID 178419650HCID 178419650, compound

Product 2

HCID 66688623N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamideHCID 866632344-[(R)-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylic acid, phenyl ester

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

To a stirred solution of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 0.1 g) in tetrahydrofuran (1.5 mL) within a microwave vial was added N,N-diisopropylethylamine (130 μL) and 4-[(R)-aminophenylmethyl]-1-piperidinecarboxylic acid, phenylmethyl ester (98 mg). The reaction was heated at 110° C. for 60 minutes within a microwave. The reaction was cooled to room temperature before the addition of cyclopropylamine (0.13 mL) and cyclopentylmagnesium bromide (2M in diethyl ether, 1 mL) dropwise. After stirring for 30 minutes, ethanol (1 mL) was added followed by ethyl acetate. The solvent was washed with water, and brine, then dried (Na2SO4), filtered and the solvent removed. The product was dissolved in t-butanol (2 mL) followed by the addition of 1,4-cyclohexadiene (1 mL) and 10% Pd on carbon (30 mg). The reaction mixture was heated within a microwave at 120° C. for 30 minutes, cooled to room temperature, filtered and purified by preparative HPLC (Gemini column, 0.1% trifluoroacetic acid:acetonitrile eluent) to afford N-cyclopropyl-4-methyl-3-[2-oxo-3-[[(R)-phenyl-4-piperidinylmethyl]amino]-1(2H)-pyrazinyl]-benzamide (58 mg) and 4-[(R)-[[4-[5-[(cyclopropylamino)carbonyl]-2-methylphenyl]-3,4-dihydro-3-oxopyrazinyl]amino]phenylmethyl]-1-piperidinecarboxylic acid, phenyl ester (19 mg).

Workup

  1. washThe solvent was washed with water, and brine
  2. dry with materialdried (Na2SO4)
  3. filtrationfiltered
  4. customthe solvent removed
  5. dissolutionThe product was dissolved in t-butanol (2 mL)
  6. additionfollowed by the addition of 1,4-cyclohexadiene (1 mL) and 10% Pd on carbon (30 mg)
  7. temperatureThe reaction mixture was heated within a microwave at 120° C. for 30 minutes
  8. temperaturecooled to room temperature
  9. filtrationfiltered
  10. custompurified by preparative HPLC (Gemini column, 0.1% trifluoroacetic acid:acetonitrile eluent)

Sources & evidence

ORD record
ord-183d135755ab4ad6a80a56958c5aeab1
Source dataset
uspto-grants-2012_04
Patent number
US08163905B2

Reaction notes

Loading…